The pathogenesis of RA, a disabling disease that disproportionately affects women, remains incompletely understood. Early diagnosis and treatment strategies are critical to minimize disability from joint destruction. The identification of individuals at high risk for disease could lead to prevention during the pre-clinical period when patients are asymptomatic. Premature immunosenescence with aberrant recognition of self-antigens may be central to RA development. Autoantibodies to citrullinated peptides are increasingly recognized as specific biomarkers, and potentially contributing agents of severe, erosive, and hereditary RA, and may be detectable years prior to RA. The fine specificity of this family of autoantibodies is beginning to be understood, as is their relationship to smoking and systemic inflammation in RA pathogenesis. Smoking, early systemic inflammation and oxidative stress are related to RA risk. Work by other groups has shown that telomere shortening, determined in part by genetic factors and in part by aging, smoking, systemic inflammation and oxidative stress, is increased in RA subjects. Telomere shortening could be a potential biomarker associated with subsequent RA development, but it is not known whether telomeres are shortened prior to RA onset, nor whether this shortening is related to future RA risk. Past studies examining telomere shortening in RA have been small, with retrospective or cross-sectional designs. They have relied upon laboratory abnormalities in subjects affected with RA compared to controls and could not address whether abnormalities predate RA onset. The goals of the proposed investigations are to advance understanding of RA etiology and to enhance prediction of this serious disease. These investigations are designed to address the important questions of whether telomere shortening and specific new anti-citrullinated peptide autoantibodies are associated with future risk of RA in women. The Nurses' Health Study prospective cohorts with over 240,000 participants followed since 1976 contain the largest population of women with banked blood samples and detailed exposure data collected years prior to RA onset. These unique cohorts lend themselves perfectly to the investigation of telomere length and novel citrullinated peptide antibodies as biomarkers for RA development. We will investigate preclinical abnormalities in telomere length and novel autoantibodies within time intervals between blood draw and RA onset. We will employ causal pathway analyses to investigate causal relationships between newly identified and replicated telomere length-associated and RA-associated genetic variants, novel anti-citrullinated peptide autoantibodies, biomarkers of systemic inflammation, telomere length and RA susceptibility. The potential role of telomere shortening in the development of RA is a novel and unanswered question and these innovative studies promise to furnish extremely important information about RA pathogenesis and risk prediction. PUBLIC HEALTH RELEVANCE: The cause of rheumatoid arthritis (RA), a disabling autoimmune disease, is incompletely understood. Antibodies to specific modified peptides have recently been found to be markers of severe, erosive, and hereditary RA, and may be detectable years prior to RA. Telomeres, repeated sequences at the ends of chromosomes, shorten with age, and have been reported to be shorter in people with RA compared to healthy individuals. The goal of these studies is to comprehensively examine telomere length and novel specific autoantibodies in relation to RA risk to understand whether these markers independently predict RA or reflect other risk factors, such as smoking or systemic inflammation.